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The synthesis of new pyrrolocarbazoles substituted at N-1/N-10 positions is described. All the compounds tested demonstrated moderate to high Pim-1/Pim-3 kinase inhibitory potency. The most active inhibitors identified in this series (3, 17) have an alkyl chain bridging the N-1 and N-10 positions. These compounds (3, 17) exhibited apoptosis-inducing activity toward acute myeloid leukemia IPC-81 cells, but not toward normal fibroblasts., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The Pim protein kinases (provirus insertion site of Moloney murine leukemia virus) have been identified as important actors involved in tumor cell survival, proliferation, migration and invasion. Therefore, inhibition of Pim activity by low molecular weight compounds is under investigation as a part of anticancer therapeutic strategies. We have synthesized a series of pyrrolo[2,3-a]carbazole derivatives that significantly inhibited Pim protein kinases at submicromolar concentrations. Particularly, benzodiazocine derivative 1 potently inhibited Pim-1 and -3 isoforms in in vitro kinase assays (IC50 8 nM and 13 nM, respectively), whereas Pim-2 activity was less affected (IC50 350 nM). We show here that no inhibitory effect of 1 was detectable at 1 µM against other 22 serine/threonine and tyrosine kinases. In addition, 1, possessing a planar pyrrolocarbazole scaffold, demonstrated no significant binding to DNA, nor was it a potent topoisomerase I inhibitor, suggesting that 1 is likely to be highly selective for Pim-1 and -3. Importantly, whereas 1 exerted a negligible cytotoxicity for human colon carcinoma HCT116 cell line at concentrations >10 µM within 72 h of cell exposure, it synergized at nontoxic concentrations with the antitumor drug doxorubicin (Dox) in killing HCT116 cells: IC50 of Dox alone and Dox+1 were ~200 nM and ~25 nM, respectively. These data strongly suggest that 1 emerges as a prospective antitumor drug candidate due to its selectivity to individual Pim protein kinases and the ability to potentiate the efficacy of conventional chemotherapeutics.

New 1,6-dihydropyrazolo[4,3-c]carbazoles and 3,6-dihydropyrazolo[3,4-c]carbazoles were prepared and evaluated for their Pim kinase inhibitory potencies as well as their antiproliferative activities toward two prostatic cancer cell lines. Pyrazolocarbazole 15a was found to be a potent Pim kinase modulator with inhibitory potency toward the three isoforms. Compound 6c strongly inhibited Pim-3 with weaker effect toward Pim-1 and Pim-2, and thus could be used as an interesting molecular tool to study Pim-3 biological functions., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Pyrrolo[2,3-a]carbazole-3-carbaldehydes are potent Pim kinase inhibitors with in vitro antiproliferative activities. In the present study, we report the synthesis and biological activities (Pim kinase inhibition and in vitro antiproliferative potency) of new 4-substituted pyrrolo[2,3-a]carbazoles. The results demonstrated that the Pim kinase inhibitory potency (especially Pim-3) can be conserved for pyrrolo[2,3-a]carbazoles bearing a methoxycarbonyl group at the 4-position without a formyl at the 3-position. Moreover, compound 27 that was found to be active against Pim-1 and Pim-3 kinases showed antiproliferative activities in the micromolar range., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

The synthesis of new pyrrolo[2,3-a]carbazole derivatives diversely substituted at the C-6 to C-9 positions is described. These compounds were tested for their kinase inhibitory potencies toward three kinases (Pim-1, Pim-2, Pim-3) as well as for their in vitro antiproliferative activities toward a human fibroblast primary culture and three human solid cancer cell lines (PC3, DU145, and PA 1). Moreover, molecular docking studies were performed to explain the enhanced inhibitory activity of the most active compound 3d., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)